Herpes simplex virus is a common human pathogen that causes cold sores, fever blisters, keratitis, and encephalitis. Once infected, a person retains the virus life-long and may suffer periodic recurrence of painful lesions that take place under a variety of conditions. Thus, prevention of either primary infections or recurring HSV lesions is an important public health goal. This will likely be achieved by understanding the basic immunity mechanism to HSV infection and applying those strategies to develop effective vaccines. Recently, we observed that in the mouse model system, protective immunity to HSV infection was dampened by a class of regulatory T cells (Treg). Such cells also hampered the efficacy of certain vaccine formulations directed against the virus. However, the same type of cells were beneficial in reducing immunopathological lesions caused by HSV infection. The current proposal will define the circumstancesthat result in Treg induction during primary and recall immunity to HSV infection. We shall also attempt to determine if the Treg response induced by HSV infection impacts on the level of immunity to other superinfections. Finally, a number of different strategies will be used to modulate the function of Treg cells in vivo to either increase immunity to HSV or reduce the damage resulting from HSV-induced immunopathology.